Insights into the Role of MicroRNAs in the Onset and Development of Diabetic Neuropathy
Abstract
:1. Types of Diabetes
2. Diabetes Complications
3. MicroRNAs and Diabetic Neuropathy
3.1. Diabetic Neuropathy
3.2. Functions of MicroRNAs
3.3. Role of MiRNAs in the Nervous System
3.4. MiRNAs Involved in the Pathogenesis of DN
3.5. MiRNAs Contribute in Animal Models of DN
3.6. Human Studies of MicroRNAs in DN
4. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
miRNAs | microRNAs |
DM | Diabetes mellitus |
T1D | Type 1 diabetes |
HLA | Human leukocyte antigen |
T2D | Type 2 diabetes |
IR | Insulin resistance |
ADA | American Diabetes Association |
ED | Endothelial dysfunction |
CVD | Cardiovascular diseases |
PN | Peripheral neuropathy |
NO | Nitric oxide |
TGF | Transforming growth factor |
DN | Diabetic neuropathy |
DSPN | Distal symmetric polyneuropathy |
DPN | Diabetic peripheral neuropathy |
STZ | Streptozotocin |
miRs | microRNAs |
RNAi | RNA interference |
AD | Alzheimer’s disease |
PD | Parkinson’s disease |
NF-κB | Nuclear factor κB |
MCP | Monocyte chemoattractant protein |
PTEN | Phosphatase and tensin homologue |
VEGF | Vascular endothelial growth factor |
IL | Interleukin 2 |
IKAK 1 | Interleukin-1 receptor-associated kinase 1 |
TRAF6 | Tumor necrosis factor receptor-associated kinase 1 |
ADAMTS3 | A disintegrin and metalloproteinase with thrombospondin motifs 3 |
12/15-LOX | 12/15 lipoxygenase |
DRG | Dorsal root ganglia |
DH | Dorsal horn |
CALHM1 | Calcium homeostasis modulator 1 |
P2X7 | Purinergic receptor P2X ligand gated ion channel 7 |
Podxl | Podocalyxin-like |
Hoxa1 | Homeobox A1 |
SLC17A6 | Solute carrier family 17A6 |
VGLUT2 | Vesicular-glutamate transporter 2 |
rev | Reviewed |
EVs | Extracellular vesicles |
NDNMT3A | DNA target proteins methyltransferase-3a |
NUMB | Endocytic adaptor protein |
SNAP25 | Synaptosome associated protein 25 |
GAP43 | Growth-associated protein-43 |
HG | High glucose |
PRKCI | Protein kinase C iota |
SMAD | Small mother against decapentaplegic |
CNS | Central nervous system |
SNPs | Single nucleotide polymorphisms |
CAN | Cardiovascular autonomic neuropathy |
SERPINE2 | Serine protease inhibitor E2 |
DEGs | Differentially expressed genes |
PPAR | Peroxisome proliferator-activated receptor |
AMP | Adenosine monophosphate |
AMPK | AMP-activated protein kinase |
PPARG | PPAR gamma |
SCD | Stearoyl-CoA desaturase |
CD36 | Cluster of differentiation 36 |
PCK1 | Phosphoenolpyruvate carboxykinase 1 |
ANXA9 | Annexin A9 |
ANGPTL4 | Angiopoietin like 4 |
CHI3L2 | Chitinase 3 Like 2 |
ADRBK2 | Adrenoceptor Beta 2 |
CSN1S1 | Casein Alpha S1 |
GALM | Galactose mutarotase |
EN1 | Homeobox protein engrailed-1 |
FAM89A | Family with sequence similarity 89 member A |
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miRNA | DN Model | Changes in DN | Target (s) | Reference (s) |
---|---|---|---|---|
miR-146a | DPN induced by intraperitoneal injection of STZ in HFD-fed rats | Down | IRAK1; TRAF6 | Feng Y et al., 2018 [49] |
miR-146a | Db/db mice as model of T2D and DN | Down | IRAK1; TRAF6; ADAMTS3 | Liu XS et al., 2017 [52] |
miR-146a | Db/db mice as model of T2D and DN | Down | IRAK1; TRAF6 | Wang L et al., 2014 [54] |
miR-146a | Diabetes was induced in rats by a single-dose injection of nicotinammide followed by STZ | Up | IRAK1; TRAF6 | Yousefzadeh N et al., 2015 [55] |
miR-106a | DPN model was established in mice following single injection of STZ | Down | 12/15-Lipoxygenase (12/15-LOX) | Wu Y et al., 2017 [56] |
miR-155 | DN was established in rats following injection of STZ | Up | ND | El Lithy GM et al., 2016 [57] |
miR-9 | DN was established in rats following injection of STZ | Up | CALHM1 is indirect target of miR-9 | Liu W et al., 2016 [58] |
miR-466i | DPN was induced in mice following injection of STZ | Down | IL-1β; TNF-α; IL-6 | Gong Q et al., 2015 [59] |
miR-467b | Down | |||
miR-466a | Up | IL-1β | ||
miR-128; miR-194; miR-466b; miR-98 | Up | IL-1β | ||
miR-27a | Up | IL-10 | ||
miR-194 | Up | IL-13 | ||
37 miRNAs were differently expressed in DRG | DN was established in rats following injection of STZ | 15 miRNAs were upregulated whereas 22 were downregulated | Podx1 and Hoxa1 were the most common targets | Guo G et al., 2018 [60] |
miR-190-5p | DPN model was established in mice following single injection of STZ | Down | SLC17A6 | Yang D et al., 2017 [61] |
miR-28, miR-31a and miR-130a | In vitro exosomes isolated from high glucose stimulated Swann Cells contained high levels of miRs-28, -31a, -130 | Up | NDNMT3A NUMB, SNAP25 and GAP43 | Jia L et al., 2018 [66] |
miR-29b | DN was established in rats following injection of STZ | Down | TGF-β/Smad3 | Zhang X et al., 2014 [69] |
Let-7i and miR-341 | DPN model was established in mice following single injection of STZ | Down | NF-kB | Cheng C et al., 2015 [71] |
MiRNA | Target (s) | Changes in DN Patients | Clinical Manifestations | Reference |
---|---|---|---|---|
miR-499a; -128a; -146a; -27a | ND | Polymorphisms in the miRNA gene sequence | High incidence of developing CAN and DPN in T2D | Ciccacci C et al. [72,73] |
miR-199a-3p | SerpinE2 | Up in skin biopsies | Promote coagulation in peripheral skin circulation in T2D | Li YB et al., 2017 [74] |
miR-216a | ANXA9 | Up in nerve tissue samples | Positive association with progressing DN | Li YB et al., 2016 [75] |
ANGPTL4 | ||||
CHI3L2 | ||||
miR-217 | ADRBK2 | |||
CSN1S1 | ||||
GALM | ||||
miR-377 | EN1 | |||
GAP43 | ||||
FAM89A |
MiRNA | Target Genes | Most Regulated Pathways | KEGG Pathway |
---|---|---|---|
miR-146a | IRAK1 | NF-kB signaling pathway | mmu04064 |
Toll-like receptor signaling pathway | mmu04620 | ||
MAPK signaling pathway | mmu04010 | ||
Neurotrophin signaling pathway | mmu04722 | ||
miR-146a | TRAF6 | NF-kB signaling pathway | mmu04064 |
Toll-like receptor signaling pathway | mmu04620 | ||
Neurotrophin signaling pathway | mmu04722 | ||
IL-17 signaling pathway | mmu04657 | ||
NOD-like receptor signaling pathway | mmu04621 | ||
MAPK signaling pathway | mmu04010 | ||
Ubiquitin mediated proteolysis | mmu04120 | ||
RIG-I-like receptor signaling | mmu04622 | ||
Endocytosis | mmu04144 | ||
miR-106a | 12/15-Lipoxygenase (12/15-LOX) | Arachidonic acid metabolism | mmu00590 |
miR-190-5p | SLC17A6 | Synaptic vesicle cycle | mmu04721 |
Glutamatergic synapse | mmu04724 | ||
miR-31a; miR-130a | NUMB; SNAP25 | Notch signaling pathway | mmu04330 |
Synaptic vesicle cycle | mmu04721 | ||
Insulin secretion | mmu04911 | ||
miR-29b | Smad3 | TGF-beta signaling pathway | mmu04350 |
FoxO signaling pathway | mmu04068 | ||
Wnt signaling pathway | mmu04310 | ||
Th17 cell differentiation | mmu04659 | ||
Cell cycle | mmu04110 | ||
miR-29c | PRKCI | Tight junction | mmu04530 |
Rap1 signaling pathway | mmu04015 | ||
Endocytosis | mmu04144 | ||
Insulin signaling pathway | mmu04910 | ||
miR-466i; miR-467b | TNF-α; Il-6 | NF-kB signaling pathway | mmu04064 |
Apoptosis | mmu04210 | ||
TNF signaling pathway | mmu04668 | ||
HIF-1 signaling pathway | mmu04066 | ||
PI3K-Akt signaling pathway | mmu04151 | ||
Insulin resistance | mmu04931 | ||
Toll-like receptor signaling pathway | mmu04620 | ||
NOD-like receptor signaling pathway | mmu04621 | ||
miR-466a; miR-128; -194; -466b; -98 | IL-1β | NOD-like receptor signaling pathway | mmu04621 |
NF-kB signaling pathway | mmu04064 | ||
IL-17 signaling pathway | mmu04657 | ||
Th17 cell differentiation | mmu04659 | ||
Toll-like receptor signaling pathway | mmu04620 | ||
Inflammatory mediator regulation of TRP channels | mmu04750 | ||
miR-27; miR-194 | IL-10; IL-13 | FoxO signaling pathway | mmu04068 |
TCR signaling pathway | mmu04660 | ||
IL-17 signaling pathway | mmu04657 | ||
Th1 and Th2 cell differentiation | mmu04658 | ||
miR-216a | ANGPTL4 | PPAR signaling pathway | hsa03320 |
Cholesterol metabolism | hsa04979 | ||
miR-217 | ADRBK2 GALM | Glutamatergic synapse | hsa04724 |
Glycolysis and gluconeogenesis | hsa00010 | ||
Galactose metabolism | hsa00052 |
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Simeoli, R.; Fierabracci, A. Insights into the Role of MicroRNAs in the Onset and Development of Diabetic Neuropathy. Int. J. Mol. Sci. 2019, 20, 4627. https://doi.org/10.3390/ijms20184627
Simeoli R, Fierabracci A. Insights into the Role of MicroRNAs in the Onset and Development of Diabetic Neuropathy. International Journal of Molecular Sciences. 2019; 20(18):4627. https://doi.org/10.3390/ijms20184627
Chicago/Turabian StyleSimeoli, Raffaele, and Alessandra Fierabracci. 2019. "Insights into the Role of MicroRNAs in the Onset and Development of Diabetic Neuropathy" International Journal of Molecular Sciences 20, no. 18: 4627. https://doi.org/10.3390/ijms20184627